Attention Deficit Hyperactivity Disorder (ADHD) is a common disorder of childhood associated with school failure, psychiatric co-morbidity and psychosocial disability. Family and twin studies suggest that ADHD has a substantial genetic component and, unlike other psychiatric conditions that have produced an array of conflicting results, molecular genetic research into ADHD has produced a body of work implicating several genes in the etiology of the disorder. In the first funding cycle of this grant, we have used a family- based association study to search for variants that result in increased susceptibility to ADHD for the DRD4, SLC6A3, DRD5, SNAP25 and HTR1B genes. That work has found evidence for haplotypes of the HTR1B and SNAP25 genes as increasing susceptibility to ADHD. We have resequenced the risk haplotypes in 48 ADHD affecteds, resequencing a total of 115kb identifying a total of 350 SNPs of which 200 are novel. In this proposed renewal, we plan to confirm and extend the haplotype association results for HTR1B, SLC6A3 and SNAP25 using family-based and case-control samples. Identifying true causal variants after observing haplotypic associations presents a challenge because the SNPs sampled in a given haplotype block are correlated and may not include the causal polymorphisms of interest. Our search for susceptibility variants will focus on the following genes which show sufficient evidence for association with ADHD in our sample: SLC6A3, SNAP25, and HTR1B. We will extend our project to test the hypothesis that additional genes are associated with ADHD. For each of these genes we will: 1. Select htSNPs that characterize the haplotype structure of each gene as well as SNPs reported to be associated with ADHD in previous studies;2. Genotype these htSNPs in our ADHD samples. 3. Perform family-based and haplotype-based analyses that are resistant to population stratification biases;and 4. Perform exploratory studies of ADHD phenotypes, gene-gene interaction and gene- environment interaction. We view our proposal as significant because, should we find gene variants that mediate susceptibility to ADHD, they will likely provide clues to the etiology and pathophysiology of the disorder. That, in turn, should facilitate the search for newer, more effective treatments for the disorder.